Study of Mitomycin-C Application in Laryngotracheal Stenosis

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01523275
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arms: 2
• Actual Duration (Months): 66
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a randomized, prospective, double-blind, placebo-controlled clinical trial of the use of mitomycin-C topical application as an adjunctive treatment in the endoscopic surgical treatment of patients with laryngotracheal stenosis. We hypothesize that the use of mitomycin-C improves patient outcome in the endoscopic surgical treatment of laryngotracheal stenosis.

Condition or Disease	Intervention/Treatment	Phase
Laryngeal Stenosis; Subglottic Stenosis; Tracheal Stenosis	Drug: Mitomycin -C; Other: Saline application	N/A

Detailed Description

Obstruction of the upper airway caused by laryngotracheal stenosis (LTS) often results in severe morbidity and even mortality. Treatment of LTS continues to present a challenge and a wide array of surgical techniques have been employed. Despite multiple endoscopic and/or open reconstructive procedures, patients often experience restenosis as a result of the abnormal wound-healing process that initially instigated the airway obstruction. The high rate of stenosis relapse has therefore motivated researchers to find new methods to modulate and control the wound-healing process of the airway. Although other adjuvant treatments such as steroids and antibiotics have been investigated in LTS, much attention in recent years has turned to the use of topical mitomycin-C (MMC). As a topical application, MMC has been shown to inhibit fibroblast proliferation in wound-healing processes. The use of MMC in the treatment of airway stenosis was first reported in 1998 and is now routinely used in the endoscopic management of LTS. However, despite numerous animal and human studies, the benefit of MMC in LTS patients remains questionable. While previously published retrospective data suggest that the addition of MMC improves outcome, there have been no prospective studies to directly address the efficacy of MMC in endoscopic LTS surgery. This study will be the first randomized, prospective, double-blind, placebo controlled clinical trial designed to investigate the efficacy of MMC as an adjunctive therapy to endoscopic surgical treatment in patients with LTS. In addition, the study will investigate the relationship between patient symptoms and objective pulmonary function measurements. Ultimately, the results of this study may influence the treatment and evaluation of patients with laryngotracheal stenosis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Study of Mitomycin-C Application in the Endoscopic Surgical Treatment of Patients With Laryngotracheal Stenosis
• Actual Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Feb 1, 2018
• Actual Study Completion Date: Feb 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mitomycin-C Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of MMC in the radial incisions.	Drug: Mitomycin -C; Topical mitomycin-C at a dosage of 0.4mg/ml will be applied to cottonoid pledgets and placed into the radial incisions for 3 minutes.
Placebo Comparator: Saline Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of isotonic saline in the radial incisions.	Other: Saline application; Isotonic saline will be applied to cottonoid pledgets and placed into the patient's radial incisions for 3 minutes as the placebo intervention.

Outcome Measures

Primary Outcome Measures

1. Time to Repeat Surgery [24 months]

   Length of time between surgeries for laryngotracheal stenosis during the study

Secondary Outcome Measures

1. Duration of Symptom Improvement [24 months]

   Symptom improvement was measured using the Clinical COPD Questionnaire, a 10-point patient reported symptom score. Duration of symptom improvement was defined as the time from surgery to the time that symptoms to worsened beyond a CCQ score of 1 or the time to the subsequent surgery if CCQ never exceeded 1

2. Peak Inspiratory Flow Measurement [3 months]

   Change in maximum inspiratory air flow from preoperative value to highest postoperative value within 3 months of surgery. Calculation details: Highest postoperative value within 3 months of surgery minus preoperative value.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with laryngotracheal stenosis, including subglottic stenosis or tracheal stenosis

• Patients with disease amenable to treatment with endoscopic CO2 laser radial incisions and balloon dilation

• Age greater than or equal to 18 years

Exclusion Criteria:

• Age less than 18 years

• Pregnancy

• Patients with glottic and supraglottic stenosis

• Patients with disease not amenable to treatment with endoscopic CO2 laser radial incisions and balloon dilation

• Patients with cartilaginous subglottic or tracheal stenosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF - Voice and Swallowing Clinic	San Francisco	California	United States	94115

Sponsors and Collaborators

• University of California, San Francisco

Investigators

• Principal Investigator: Katherine C Yung, MD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 27, 2018

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01523275
• Other Study ID Numbers: Laryngotracheal Stenosis
• First Posted: Feb 1, 2012
• Last Update Posted: May 22, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by University of California, San Francisco: mitomycin-C; laryngotracheal stenosis; subglottic stenosis; tracheal stenosis; endoscopic airway surgery
• Additional relevant MeSH terms: Tracheal Stenosis; Laryngostenosis; Constriction, Pathologic; Mitomycins; Mitomycin

Study Results

Participant Flow

Recruitment Details	Recruited from the UCSF Voice and Swallowing Center clinic from August 1, 2012 to February 1, 2018

Arm/Group Title	Mitomycin C	Saline
Arm/Group Description	Endoscopic dilation with topical mitomycin C	Endoscopic dilation with topical saline
Period Title: Overall Study
STARTED	6	9
COMPLETED	4	7
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Saline	Mitomycin-C	Total
Arm/Group Description	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of isotonic saline in the radial incisions. Saline application: Isotonic saline will be applied to cottonoid pledgets and placed into the patient's radial incisions for 3 minutes as the placebo intervention.	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of MMC in the radial incisions. Mitomycin -C: Topical mitomycin-C at a dosage of 0.4mg/ml will be applied to cottonoid pledgets and placed into the radial incisions for 3 minutes.	Total of all reporting groups
Overall Participants	9	6	15
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 55.6%	6 100%	11 73.3%
>=65 years	4 44.4%	0 0%	4 26.7%
Age (Years of age) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years of age]	57.1 (12.4)	48 (8.3)	53 (11.6)
Sex: Female, Male (Count of Participants)
Female	9 100%	4 66.7%	13 86.7%
Male	0 0%	2 33.3%	2 13.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 11.1%	2 33.3%	3 20%
Not Hispanic or Latino	8 88.9%	4 66.7%	12 80%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	8 88.9%	4 66.7%	12 80%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 11.1%	2 33.3%	3 20%
Age of Onset (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.2 (13.5)	44.2 (9.2)	49 (12.3)
Etiology (Count of Participants)
Idiopathic	6 66.7%	5 83.3%	11 73.3%
Granulomatosis with Polyangiitis	2 22.2%	1 16.7%	3 20%
Post-Intubation	1 11.1%	0 0%	1 6.7%
Site (Count of Participants)
Subglottis	8 88.9%	5 83.3%	13 86.7%
Trachea	1 11.1%	0 0%	1 6.7%
Subglottis and Trachea	0 0%	1 16.7%	1 6.7%
Prior laryngotracheal stenosis surgery (Count of Participants)
Yes	4 44.4%	5 83.3%	9 60%
No	5 55.6%	1 16.7%	6 40%
Average prior laryngotracheal stenosis surgeries (Surgeries) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Surgeries]	1.1 (1.5)	4 (4.9)	2 (3.5)
Prior treatment with Mitomycin C (Count of Participants)
Yes	3 33.3%	4 66.7%	7 46.7%
No	6 66.7%	2 33.3%	8 53.3%
Prior treatment with Kenalog (Count of Participants)
Yes	2 22.2%	4 66.7%	6 40%
No	7 77.8%	2 33.3%	9 60%

Outcome Measures

1. Primary Outcome

Title	Time to Repeat Surgery
Description	Length of time between surgeries for laryngotracheal stenosis during the study
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Patients who did not undergo a subsequent surgery after the initial study surgery were excluded as a surgical interval could not be calculated. There were two patients in each arm that did not have subsequent surgeries

Arm/Group Title	Saline	Mitomycin-C
Arm/Group Description	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of isotonic saline in the radial incisions. Saline application: Isotonic saline will be applied to cottonoid pledgets and placed into the patient's radial incisions for 3 minutes as the placebo intervention.	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of MMC in the radial incisions. Mitomycin -C: Topical mitomycin-C at a dosage of 0.4mg/ml will be applied to cottonoid pledgets and placed into the radial incisions for 3 minutes.
Measure Participants	7	4
Mean (Standard Deviation) [Months]	17.9 (15.7)	17.4 (12.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Mitomycin-C
	Comments
	Type of Statistical Test	Equivalence
	Comments	Analysis of 44 subjects (22 in each arm) would provide 90% power to detect a difference in the time interval to reoperation of 6 months between the two treatment arms, at an alpha level of 0.05. This difference of 6 months is clinically meaningful and is smaller than previous case series studies would suggest. However, due to poor patient accrual, the study was closed prior to reaching the desired study size.
Statistical Test of Hypothesis	p-Value	0.95
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Duration of Symptom Improvement
Description	Symptom improvement was measured using the Clinical COPD Questionnaire, a 10-point patient reported symptom score. Duration of symptom improvement was defined as the time from surgery to the time that symptoms to worsened beyond a CCQ score of 1 or the time to the subsequent surgery if CCQ never exceeded 1
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Time to symptom score (CCQ) progression was calculated for each surgery performed during the study with available CCQ data.

Arm/Group Title	Saline	Mitomycin-C
Arm/Group Description	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of isotonic saline in the radial incisions. Saline application: Isotonic saline will be applied to cottonoid pledgets and placed into the patient's radial incisions for 3 minutes as the placebo intervention.	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of MMC in the radial incisions. Mitomycin -C: Topical mitomycin-C at a dosage of 0.4mg/ml will be applied to cottonoid pledgets and placed into the radial incisions for 3 minutes.
Measure Participants	9	6
Measure Surgeries	13	9
Mean (Standard Deviation) [Months]	4.1 (6.7)	6.0 (6.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Mitomycin-C
	Comments
	Type of Statistical Test	Equivalence
	Comments	A difference of 6 months to symptom progression is clinically meaningful.
Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Peak Inspiratory Flow Measurement
Description	Change in maximum inspiratory air flow from preoperative value to highest postoperative value within 3 months of surgery. Calculation details: Highest postoperative value within 3 months of surgery minus preoperative value.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Improvement in peak inspiratory flow (PIF) was calculated for each surgery performed during the study with available PIF data

Arm/Group Title	Saline	Mitomycin-C
Arm/Group Description	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of isotonic saline in the radial incisions. Saline application: Isotonic saline will be applied to cottonoid pledgets and placed into the patient's radial incisions for 3 minutes as the placebo intervention.	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of MMC in the radial incisions. Mitomycin -C: Topical mitomycin-C at a dosage of 0.4mg/ml will be applied to cottonoid pledgets and placed into the radial incisions for 3 minutes.
Measure Participants	9	6
Measure Surgeries	14	8
Mean (Standard Deviation) [Liters per second]	1.1 (1.5)	1.3 (0.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Mitomycin-C
	Comments
	Type of Statistical Test	Equivalence
	Comments	0.5 liters per second is clinically significant.
Statistical Test of Hypothesis	p-Value	0.64
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Adverse event data was collected through study completion, which was on average of 2.3 years
Arm/Group Title	Saline		Mitomycin-C
Arm/Group Description	Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of isotonic saline in the radial incisions. Saline application: Isotonic saline will be applied to cottonoid pledgets and placed into the patient's radial incisions for 3 minutes as the placebo intervention.		Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of MMC in the radial incisions. Mitomycin -C: Topical mitomycin-C at a dosage of 0.4mg/ml will be applied to cottonoid pledgets and placed into the radial incisions for 3 minutes.
All Cause Mortality
	Saline		Mitomycin-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/6 (0%)
Serious Adverse Events
	Saline		Mitomycin-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Saline		Mitomycin-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.